Dovitinib induces mitotic defects and activates the G 2 DNA damage checkpoint

D ovitinib ( TKI 258; formerly CHIR ‐258) is an orally bioavailable inhibitor of multiple receptor tyrosine kinases. Interestingly, D ovitinib triggered a G 2 /M arrest in cancer cell lines from diverse origins including HeLa, nasopharyngeal carcinoma, and hepatocellular carcinoma. Single‐cell analysis revealed that D ovitinib promoted a delay in mitotic exit in a subset of cells, causing the cells to undergo mitotic slippage. Higher concentrations of D ovitinib induced a G 2 arrest similar to the G 2 DNA damage checkpoint. In support of this, DNA damage was triggered by D ovitinib as revealed by γ‐H2 AX and comet assays. The mitotic kinase CDK 1 was found to be inactivated by phosphorylation in the presence of D ovitinib. Furthermore, the G 2 arrest could be overcome by abrogation of the G 2 DNA damage checkpoint using small molecule inhibitors of CHK 1 and WEE 1. Finally, D ovitinib‐mediated G 2 cell cycle arrest and subsequent cell death could be promoted after DNA damage repair was disrupted by inhibitors of poly( ADP ‐ribose) polymerases. These results are consistent with the recent finding that D ovitinib can also target topoisomerases. Collectively, these results suggest additional directions for use of D ovitinib, in particular with agents that target the DNA damage checkpoint.